Pearls of Wisdom: Treatment Options for Diabetic Peripheral Neuropathic Pain

Randall is a 62-year-old man with longstanding type 2 diabetes that is well controlled (A1c = 7.0) with metformin and glimepiride.

He has been troubled with diabetic peripheral neuropathic pain (DPNP) for the last 6 months. He complains that the pain intensity is a 7 on a 10-point scale and it seems to worsen at night or with exercise. As a result, he experiences interrupted sleep and due to the pain, his attempts to exercise are often fruitless. 

He has tried a variety of interventions for his DPNP: 

• Amitriptyline at a low dose (25 mg) was somewhat helpful, but at higher doses, he experienced orthostatic hypotension. 
• Gabapentin was modestly effective, but caused him problematic sedation. 
• Venlafaxine had some beneficial effects but only at high doses (>225 mg/d), which elevated his blood pressure. 

Randall has been prescribed acetaminophen with codeine, but is reluctant to use the medication. 

In a patient with DPNP that has not been adequately controlled with tricyclics, gabapentin, and venlafaxine, what might be an effective next step?

A. Nitroglycerin spray (eg, nitrolingual)
B. An oral alpha blocker (eg, doxazosin)
C. An oral sodium glucose co-transporter 2 inhibitor (eg, canagliflozin)
D. A glucagon-like peptide-1 receptor agonist (eg, exenatide)

 What is the correct answer?
(Answer and discussion on next page)

Louis Kuritzky, MD, has been involved in medical education since the 1970s. Drawing upon years of clinical experience, he has crafted each year for almost 3 decades a collection of items that are often underappreciated by clinicians, yet important for patients. His “Pearls of Wisdom” as we like to call them, have been shared with primary care physicians annually in an educational presentation entitled 5TIWIKLY (“5 Things I Wish I Knew Last Year”…. or the grammatically correct, “5 Things I Wish I’d Known Last Year”).

Now, for the first time, Dr Kuritzky is sharing with the Consultant360 audience. Sign up today to receive new advice each week.

Answer: Nitroglycerin spray

Diabetic peripheral neuropathic pain (DPNP) can be a serious burden to patients with type 2 diabetes (T2DM). Not only can the pain be severe, but it also tends to worsen at night (thus interrupting sleep) and with exercise.

Because most of our T2DM patients are overweight or obese, exercise goals are important. DPNP can effectively defeat the patient’s ability to exercise.

Our patient has already tried some of the commonly used medications for DPNP; economic constraints preclude some of the more expensive prescription agents. Note: the only 2 agents that are FDA-approved for DPNP are duloxetine (Cymbalta) and pregabalin (Lyrica).

What else might be worth a try? Perhaps a nitroglycerin spray.^{1
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RELATED CONTENT
Diabetic Peripheral Neuropathic Pain: Effective Management
Exercise for Patients With Diabetic Peripheral Neuropathy
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The Research

DPNP is considered a “microvascular complication” of diabetes because it reflects dysfunction of the vasonervorum—the microvasculature that supplies the nerves. As a result, less nitric oxide is available to nourish nerves. Animal studies have demonstrated that decreasing nitric oxide availability to nerves results in hyperalgesia.

Researchers performed a double blind randomized placebo controlled trial¹ with 2 crossover periods in which persons with longstanding DPNP (mean of 2.6 years) were treated with either placebo or nitroglycerin spray. Because previous treatment methods for DPNP were not halted at the start of the study, the initial pain scores (5.5 on a 10-point scale) may appear modest.

DPNP: Topical Nitroglycerin¹

Patients were instructed to apply a single spray of nitroglycerin (or placebo) to the site of their pain each night.

DPNP: Topical Nitroglycerin¹

At the conclusion of the trial, those who used nitroglycerin spray reported a statistically significant 2-point decrease in pain, and those using placebo showed no change. Several individual patient commentaries were favorable as well.

DPNP: Topical Nitroglycerin: Results¹

Nitroglycerin, when applied to the skin (eg, nitropaste used for angina) may cause headaches or hypotension, but nitroglycerin spray—which is intended for oral absorption—is poorly absorbed through the skin, hence minimizing any systemic toxicities.

What’s the “Take Home”?

Nitroglycerin spray is a novel treatment for DPNP that matches pathophysiologic defects to which the neuropathy is attributed. It is an inexpensive, minimally systematic method to reduce pain while (hopefully) simultaneously improving sleep and the ability to enjoy pain-free exercise.

Reference:

1. Yuen KCJ, Baker NR, Rayman G. Rx of Chronic Painful Diabetic Neuropathy with Isosorbide Dinitrate Spray. Diabetes Care. 2002;254:1699-1703.